ABSTRACT Over the past decade, hypervirulent epidemic strains of C. difficile (typified by NAP1/027) have emerged. In addition to toxins A and B produced by classical strains, the epidemic strains produce an additional third toxin called binary toxin (CDT). Our lab has identified CDT toxin as a virulence factor that increases detrimental inflammation via the toll-like receptor-2 (TLR2) pathway. My preliminary data indicates interleukin-33 (IL-33) treatment can protect from CDT mediated mortality during NAPI/027 C. difficile infection. The goal of this fellowship is to determine how CDT interacts with and activates the TLR2 complex and to understand how IL-33 protects from CDT-mediated mortality during hypervirulent C. difficile infection. We will test the hypothesis that CDT interacts with TLR2 and/or TLR1 and TLR6 to activate detrimental inflammation (Aim 1) and test how IL-33 dampens inflammation in the gut to protect from CDT virulence. (Aim 2). Ultimately, this research project sets out to delineate novel, antibiotic alternative targets to treat epidemic C. difficile infection as one in five patients relapse after receiving antibiotic therapy. The research project proposed will be carried out in conjunction with a rigorous training plan composed of the following: 1) integrative coursework and interactive training 2) participation in research meetings and seminars 3) participation in scientific conferences 4) professional development and 5) community outreach. The combination of proposed research along with an active training plan will yield meaningful contributions to the field and the training required to excel as a successful infectious disease and immunology researcher.